Our research objective is the investigation of the biochemical and genetic basis of the variations found in the aging rate and maximum lifespan potential observed among the different mammalian species. Particular emphasis is placed on humans which appear to have the lowest aging rate and longest maximum lifespan potentials of all mammals. Past work of our laboratory has indicated that aging may be a result of the loss of proper gene expression in cells and this has led to formulation of the dysdifferentiative hypothesis of aging. Recent work to further test this hypothesis has involved studies of oncogene expression and methylation patterns of DNA with age in mouse and human tissues. An age-dependent decrease in the amount of 5-methyl cytosine content in DNA of mouse tissues with age has been found. We have also examined the possibility that active oxygen species might be important in destabilizing proper gene expression and that in turn endogenous antioxidants may be gene stabilizing agents. Tissues from longer-lived species were found to have higher levels only of specific types of antioxidants but to be less sensitive to autoxidation. Taken together, these results continue to support the concept that aging is accompanied by cellular dysdifferentiative processes and that longevity may be governed in part by endogenous antioxidants which act to stabilize proper gene expression.